Autoimmunity
Abstract
Intestinal acute graft-versus-host disease (aGVHD) is a common life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Although tissue-resident memory T (TRM) cells are thought to play a pathophysiological role in animal models of aGVHD, little is known about the role of distinct subsets of TRM cells in human intestinal aGVHD. Herein, we combined multiplex immunohistochemical staining with single-cell RNA sequencing to elucidate the differentiation trajectory, lineage commitment, clonal expansion, and functional properties of distinct CD8+ TRM cell subsets in human intestinal aGVHD. We identified a predominant GZMK+CD8+ TRM subset, characterized by the GZMK and CD49A markers. Intestinal aGVHD was associated with infiltration of GZMK+CD8+ T cells with TRM features, which showed enhanced clonal expansion, IFN signaling pathway–associated proinflammatory pathway expression, and lineage bifurcation differentiation properties. High GZMK+CD8+ TRM subset infiltration was associated with greater human intestinal aGVHD severity and poor prognosis. Together, our studies highlight the importance of the GZMK+CD8+ TRM subset in human intestinal aGVHD, and interest for designing GZMK+CD8+ TRM cell–targeted therapies.
Authors
Yiming Sun, Yutong Xue, Chenyuyao Song, Xinyu Liu, Ruoyang Shao, Zhiping Fan, Ren Lin, Fen Huang, Na Xu, Li Xuan, Min Dai, Jing Sun, Qifa Liu, Hua Jin
Abstract
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED/APS-1) is a monogenic autoimmune disorder of impaired central tolerance classically diagnosed by the presence of 2 out of 3 classic triad manifestations: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenal insufficiency. However, many patients develop non-triad manifestations years earlier, delaying recognition and care. In 2016, we proposed expanded diagnostic criteria incorporating 3 early clinical manifestations — APECED rash, autoimmune enteritis, and enamel hypoplasia — based on observations in 35 North American patients. Here, we provide further support for the clinical utility of these expanded diagnostic criteria in independent cohorts of 57 American and 12 European patients enrolled in a prospective natural history study at the NIH. Across all cohorts, the expanded diagnostic criteria decreased the time to diagnosis by half relative to the classic diagnostic criteria. Patients exhibited an enrichment of early non-endocrine autoimmune manifestations, underscoring disease heterogeneity and the potential for developing organ-specific autoimmunity before endocrine failure. These findings demonstrate the clinical utility of the expanded APECED diagnostic criteria and support the notion that their adoption might enable earlier disease recognition and timely immunomodulatory therapy to improve long-term outcomes.
Authors
Elise M.N. Ferré, Joseph Pechacek, Monica M. Schmitt, Taura Webb, Heather Moorman, Thomas DiMaggio, Princess Barber, Vasielios Oikonomou, Stacey R. Rose, Peter D. Burbelo, Lindsey B. Rosen, Amy P. Hsu, Jennifer Stoddard, Shakuntala Rampertaap, Sergio D. Rosenzweig, Anjali Rai, Maria Teresa Magone, Chantal Cousineau-Krieger, Niki M. Moutsopoulos, Pamela J. Gardner, Heidi H. Kong, Leslie Castelo-Soccio, Ariane Soldatos, Katherine R. Calvo, Meryl Waldman, Behdad Afzali, Stefania Pittaluga, David Kleiner, Steven M. Holland, Kevin Fennelly, Jill Rothschild, Bryce A. Seifert, Magdalena Walkiewicz-Yvon, Theo Heller, Karen Winer, Michail S. Lionakis
Abstract
Systemic sclerosis (SSc) is a rare autoimmune disease characterized by vasculopathy and fibrosis of the skin and internal organs. Individuals with SSc often suffer from chronic acid reflux and dysphagia due to loss of esophageal motility. However, the pathogenesis of esophageal dysmotility in SSc is poorly understood. To determine whether distinct changes in esophageal epithelial cells contribute to esophageal involvement in SSc, we investigated the stratified squamous esophageal epithelium from proximal and distal biopsies using single-cell RNA sequencing (n=306,372 cells) in individuals with SSc compared those with gastroesophageal reflux disease (GERD) and healthy controls. The proportion of epithelial cells in the apical, superficial compartment of the esophageal epithelium was reduced in SSc (9.4% vs 21.6% in HCs). Differential gene expression in SSc was primarily limited to the superficial compartment (3,572 genes vs. 232 in all other compartments, based on pseudobulk analysis), with significant upregulation of extracellular matrix and keratinization genes. These cellular and molecular changes in SSc were highly correlated with those seen in GERD, indicating they were secondary to reflux; however, their magnitudes were more pronounced in the proximal esophagus, suggesting that esophageal dysmotility leads to greater proximal acid exposure, which may contribute to aspiration. SSc-specific gene dysregulation implicated immunoregulatory pathways likely pertinent to pathogenic mechanisms. Ligand-receptor interaction analysis revealed enhanced pro-fibrotic signaling between fibroblasts and epithelial cells in SSc. Cell type localization and SSc-specific changes were confirmed by spatial molecular imaging. By offering a comprehensive view of transcriptional dysregulation at single-cell resolution in human esophageal epithelial cells in SSc compared to GERD and healthy tissue, this work clarifies the state of epithelial cells in SSc-induced esophageal dysfunction.
Authors
Matthew Dapas, Margarette H. Clevenger, Hadijat-Kubura M. Makinde, Tyler Therron, Dustin A. Carlson, Mary Carns, Kathleen Aren, Cenfu Wei, Kainat Mian, Lutfiyya N. Muhammad, Carrie L. Richardson, Parambir S Dulai, Monique Hinchcliff, John E. Pandolfino, Harris R. Perlman, Deborah R. Winter, Marie-Pier Tetreault
Abstract
In chronic beryllium disease (CBD), elevated levels of the inflammatory chemokines CCL3 and CCL4 in the lungs coincide with expanded populations of CD4+ T cells specific to beryllium (Be)-modified peptides derived from these chemokines. Here, we generated HLA-DP2 transgenic (Tg) CCL3-deficient mice (CCL3-/-) that also lack CCL4 to investigate their role in disease development. Be-exposed CCL3-/- mice maintained normal numbers of lung macrophages and dendritic cells (DCs) but exhibited significantly reduced total and HLA-DP2-CCL/Be tetramer-specific CD4+ T cells, IFN-γ-producing CD4+ T cells, and peribronchovascular aggregates, consistent with attenuated inflammation. CCL3 was predominantly expressed in macrophages and DCs, and bone marrow chimera studies confirmed that hematopoietic-derived DCs are the key regulators of CCL/Be-specific CD4+ T cell responses. RNA sequencing of lung-resident CCL4/Be tetramer-positive CD4+ T cells revealed a transcriptional profile enriched for inflammatory and cholesterol-metabolism pathways, with elevated expression of Ifng, Tnf, and Il17a. Moreover, Be-exposed HLA-DP2 Tg mice lacking TNF-α or treated with peptide-MHCII CAR-T cells targeting CCL4/Be-specific CD4+ T cells showed reduced T cell responses and cellular aggregates. These findings demonstrate that CCL3 and CCL4 promote CCL/Be-specific CD4+ T cell responses and highlight peptide-MHCII CAR-T cells as a novel strategy for depleting self-peptide/Be-specific CD4+ T cells in CBD.
Authors
Michael T. Falta, Masoom Raza, Caley J. Nevienski, Tonya M. Brunetti, Rui Fu, Rebecca M. Tucker, Joseph M. Gaballa, Faiz Minhajuddin, Kibrom M. Alula, Alberto Dinarello, Douglas G. Mack, Allison K. Martin, Joseph C. Onyiah, Michael Yarnell, Prashanth Francis, Terry J. Fry, Lisa A. Maier, Andrew P. Fontenot, Charles A. Dinarello, Shaikh M. Atif
Abstract
Synovial hyperplasia is a hallmark of rheumatoid arthritis (RA), yet its mechanism remains unclear. RA synovium exhibits metabolic shift, characterized by upregulated glycolysis and enhanced lactate production. In this study, we elucidated the mechanism underlying the roles of lactate metabolism and protein lactylation in RA pathology. In patients with RA, both lactate production and protein lactylation were elevated and showed a positive correlation with clinical disease activity. These changes were further implicated in driving synovial proliferation. Among the lactylated proteins, Cysteine-rich intestinal protein 1 (CRIP1) exhibited a marked increase in modification and played a central role in promoting synovial proliferation. Mechanistically, CRIP1 underwent MOF-mediated lactylation in RA synovial fibroblasts. Lactylated CRIP1 hijacked the cell-cycle regulator p21, disrupting its interaction with cyclin-dependent kinase 2 (CDK2), thereby facilitating the G1/S phase transition. Functionally, AAV-mediated delivery of a lactylation-deficient CRIP1 K49R significantly reduced synovial proliferation compared with WT CRIP1. Peptide-based interventions targeting CRIP1 K49 lactylation effectively inhibited synovial hyperplasia and disease severity in both Collagen II–induced arthritis (CIA) and humanized NSG chimeric models. Collectively, CRIP1 protein lactylation drives synovial proliferation in RA by hijacking p21 from CDK2, thereby facilitating cell cycle progression. Targeting this pathway may serve as a promising strategy for RA.
Authors
Meican Ma, Yu Zhou, Qianlin Li, Zhao Wang, Shangqi Guan, Xiaoxue Wang, Han Zhao, Zhenke Wen, Ting Liu, Fenghong Yuan
Abstract
Community-acquired pneumonia is a major cause of morbidity and mortality globally. Specific molecular endotypes are currently not well defined, and different viral or bacterial pathogens may trigger specific host responses and pathogenic mechanisms. We performed longitudinal proteomic profiling of bronchoalveolar lavage fluid and plasma from bacterial, influenza, and SARS-CoV-2–driven pneumonia. Our analysis revealed highly pneumonia type–specific proteomic signatures, including COVID-19–specific antibodies locally produced in the lung. These antibodies showed biased immunoglobulin V–domain usage, linked to a CD69/CD83 plasma cell state associated with disease severity and degree of autoimmunity. Using mass spectrometry–driven autoantibody profiling in 2 independent COVID-19 cohorts, we identified 177 putative autoantibodies targeting extracellular matrix, nuclear, and immune-related proteins. Of note, temporal changes in autoantibody profiles correlated with clinical markers of inflammation, organ dysfunction, and duration of hospitalization. These findings highlight the autoimmune aspects of COVID-19 and provide potential biomarkers and therapeutic targets to help improve patient outcomes.
Authors
Anna Semenova, Taylor A. Poor, Johannes B. Müller-Reif, Sai Rama Sridatta Prakki, Phillip Geyer, Martin Mück-Häusl, Rogan A. Grant, Luke Rasmussen, Lesca M. Holdt, Daniel Teupser, Matthias Mann, Ali Ö. Yildirim, Richard G. Wunderink, Alexander V. Misharin, Ben D. Singer, G.R. Scott Budinger, Theodore S. Kapellos, Herbert B. Schiller
Abstract
Stem cell–derived β cells offer a promising approach for type 1 diabetes (T1D) treatment. However, the processes of graft infiltration and rejection by immune cells remain poorly understood in humans. In this study, autologous or allogeneic stem cell–derived islets (SC-islets) were transplanted in human immune system mice and analyzed 14 to 18 weeks later. Imaging mass cytometry revealed unique characteristics of SC-islet grafts, including a high percentage of glucagon+ cells and the presence of cysts and CD57+ enterochromaffin cells, features not typically observed in endogenous or transplanted allogeneic primary pancreatic islets. Allogeneic SC-islet grafts exhibited heavy immune infiltration, cell proliferation, and pro-fibrotic processes, whereas autologous grafts showed minimal infiltration and little fibrosis. In some mice, autologous T cells expressing islet antigen-reactive (IAR) T cell receptors (TCRs) were adoptively transferred. Three weeks after transfer, autologous grafts injected with IAR-TCR+ T cells showed negligible immune infiltration, even though IAR-TCR+ T cells were detected in the spleen. Under the conditions tested, human SC-islet grafts were not rejected by an autologous immune system, even in the presence of autoreactive T cells, pointing to several limitations that remain to be addressed for a model of spontaneous autologous SC-islet infiltration and destruction.
Authors
Camillo Bechi Genzano, Giorgia Zanetti, Qian Du, Daniel Traum, Deeksha Lahori, Grant M. Downes, Sakshi A. Bhatele, Xiaolan Ding, Kyle D. Apley, Rebuma Firdessa Fite, Matthew Ishahak, Enrique Eduardo Sanchez-Castro, Jeffrey R. Millman, Yiming Luo, Klaus H. Kaestner, Cory Berkland, Dieter Egli, Megan Sykes, Remi J. Creusot
Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune disease, yet the molecular basis underlying this variability remains incompletely understood. We profiled the plasma proteome in 260 SLE patients and 86 healthy volunteers (HVs) using the SomaScan v4.1 platform, quantifying 7,288 analytes corresponding to 6,595 unique proteins. We identified 215 proteins that were robustly differentially abundant between SLE patients and HVs in both discovery (n=207 SLE, n=45 HVs) and validation sets (n=53 SLE, n=41 HVs). Within-cases analyses identified 421 proteins associated with disease activity. Network-based clustering delineated correlated protein modules, including an interferon-associated module and a renal-associated module. Autoantibody-stratified analyses further uncovered distinct proteomic endotypes: positivity for antibodies targeting RNA-binding proteins (anti-Sm, anti-Ro-60, anti-RNP68, anti-RNP-A) was associated with increased interferon-stimulated protein levels (e.g., MX1, ISG15, CXCL10), independent of disease activity. Anti-Sm, anti-RNP-A and anti-Ro52 antibodies were associated with reduced plasma levels of their respective autoantigens. Anti-dsDNA antibodies were associated with elevated levels of CD40 ligand (CD40LG) and the neutrophil protease proteinase-3. Moreover, we identified an association between CD40LG and disease activity specific to the anti-dsDNA positive subgroup. Together, these data define plasma protein signatures of SLE and disease activity, highlight autoantibody-specific molecular phenotypes, and provide a basis for precision medicine.
Authors
Geoffrey H. D. Leung, Charlotte Bottomley, Norzawani Buang, Robert T. Maughan, Benjamin J. Whittle, Boroumand Zeidaabadi, Yun-Ju Huang, Tabitha Turner-Stokes, Marie Condon, Liz Lightstone, Tom Cairns, Marina Botto, Matthew C. Pickering, James E. Peters
Abstract
In multiple sclerosis (MS) lesions, CD8 T cells outnumber CD4 T cells, suggesting that they contribute to MS pathology. However, little is known about the role of CD8 T cells in MS, partly due to the prevalent use of experimental autoimmune encephalomyelitis (EAE) models mediated by CD4 T cells, which have limited involvement of CD8 T cells. Importantly, MS and EAE differ in both their distribution of CNS lesions and neurologic deficits, indicating differences in CNS inflammation. MS lesions are more commonly found in the brain, whereas EAE lesions are more frequent in the spinal cord. Additionally, neurologic deficits in MS rarely parallel the ascending paralysis typical for CD4 T cell–mediated EAE (CD4-EAE). In contrast, CD8-EAE models suggest that CD8 T cells preferentially cause brain inflammation; however, little is known about how brain and spinal cord inflammation may differ, or how CD8 T cells contribute to these differences. We have established an adoptive CD8-EAE mouse model characterized by brain-centered inflammation, ataxia, and weight loss. CNS inflammation in the brain and spinal cord differed in immune cell numbers, cellular composition, and inflammatory signatures. CD8-EAE could be suppressed by blocking IFN-γ, and exacerbated by blocking PD-1, with concomitant changes in the numbers of CNS-infiltrating monocytes. Most CD8 T cells in the CNS were CD11c+, suggesting that they are the pathogenic subset. We describe a robust CD8-EAE model, identify differences between brain and spinal cord inflammation, and characterize mechanisms that control CD8 T cell–mediated neuroinflammation, thereby furthering understanding of EAE and MS.
Authors
Daniel Hwang, Gholamreza Azizi, Larissa Lumi Watanabe Ishikawa, Maryam Seyedsadr, Arin Cox, Soohwa Jang, Ezgi Kasimoglu, Abdolmohamad Rostami, Guang-Xian Zhang, Bogoljub Ciric
Abstract
Fibroblast-like synoviocytes (FLSs) are crucial in driving synovial inflammation and joint damage in rheumatoid arthritis (RA). This study explored the functions and underlying mechanisms of GALNT1-mediated O-glycosylation, which is markedly upregulated in RA FLSs, in synovial aggression and subsequent experimental joint damage. Targeted suppression of GALNT1 effectively curtailed migration and invasion in RA FLSs and mitigated arthritis severity in a rat collagen-induced arthritis (CIA) model. Mechanistically, NEK9 was identified as a pivotal substrate and downstream effector of GALNT1, affecting the aggressive phenotype of RA FLSs. In vitro experiments further demonstrated that O-glycosylation of NEK9, mediated by GALNT1, promotes the pathogenic phenotype of RA FLSs by promoting cytoskeleton reorganization and restraining excessive endoplasmic reticulum (ER) stress activation. Our study provides mechanistic insights into the activation of RA FLSs and identifies GALNT1 as a potential therapeutic target for RA.
Authors
Yaoyao Zou, Haobo Lin, Jianling Su, Jieying Wang, Qin Zeng, Tianxiao Feng, Yunxia Lei, Jianda Ma, Hudan Pan, Hanshi Xu, Lie Dai, Yang Li
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